As a method for separating and obtaining an optinal component in a mixture, a simulated moving bed method (hereinafter, also referred to as “SMB method”) involving continuously supplying an eluant and a material solution to an endless flow passage including a plurality of columns connected in series to each other and continuously discharging the eluant from the endless flow passage using an SMBC separation system is known. The optical resolution by the SMB method is drawing attention particularly in the medical and pharmaceutical fields. In the case of producing a product that is required to have quality of very high purity such as pharmaceutical products by the SMB method, the productivity may be degraded remarkably due to the slight interference causing a decrease in purity of a component to be separated.
For example, according to the optical resolution by liquid chromatography using columns filled with a filler having a small particle size, a component separated in the columns is generally present in a thick solution state represented by a narrow peak at the time of detection, when a material solution is supplied intermittently. When the eluant containing a component separated in this state passes through a portion (also referred to as “liquid accumulation portion”) where the residence of a solution is liable to occur due to the enlargement, division, and bend each of which is formed in a flow passage having no separating function of a piping, a valve, a pump, etc. in the flow passage, the separated component diffuses in accordance with the shape and size of the liquid accumulation portion. Therefore, the inclusion of a liquid accumulation portion in a flow passage through which a separated component flows is liable to degrade the separation performance. Thus, according to the SMB method, it is desired that an endless flow passage in which the separation of a component is performed repeatedly do not include a liquid accumulation portion or a liquid accumulation portion be decreased in size as much as possible.
Further, regarding the SMB method, generally, it is generally considered to be desired to minimize the use amount of a filler while satisfying the separation performance of the filler as much as possible by using a filler having a particle size of about 20 to 25 μm (see, for example, Non Patent Literature 1). Further, as means for further enhancing the productivity of the production by separation of a component according to the SMB method, the following attempt has been made: for example, by reducing the number of columns to be set in an endless flow passage or by shortening the fill length of a filler to fill the columns (see, for example, Patent Literature 5), the pressure loss occurring in the columns per unit flow rate of an eluant is decreased while the flow rate of the eluant is increased, and the amount of the eluant passing through the columns per unit time is increased while the pressure loss applied to the entire columns is suppressed, and thus, the productivity per SMBC separation system is enhanced.
However, according to such means, the capacity of a liquid accumulation portion becomes larger relative to the capacity of a filler, i.e., the capacity of a flow passage having a separating function per SMBC separation system. Therefore, the influence by the diffusion of a component separated in an eluant in the liquid accumulation portion increases further, which may degrade the separation performance, resulting in the decrease in productivity.
As means for minimizing the diffusion of a component by the liquid accumulation portion as much as possible, for example, it is known to provide a valve designed so as to reduce a liquid accumulation portion in a flow passage of an eluant (see, for example, Patent Literature 1). This valve can withstand conditions of a high flow rate of an eluant and a high pressure in an SMBC separation system, however, the use of such special equipment increases a cost incurred in the SMBC separation system, which may influence the production cost of a separated component.
On the other hand, according to the SMB method, usually, the supply position of an eluant and a material solution, and the discharge position of the eluant move so as to make a circuit of an endless flow passage. It is known that, according to the SMB method, in order to perform appropriate separation, the flow rate of a pump provided in an endless flow passage and circulating an eluant in the endless flow passage is controlled step by step in accordance with the supply and discharge positions. An example of the SMB method including such a control includes a method for controlling the flow rate of the pump within 1 to 2% of a set value of the flow rate in each step (see, for example, Patent Literature 2).
According to the stepwise control of a flow rate, when the control value of the flow rate of a pump is switched, an actual flow rate of an eluant may exceed largely the control value, and thereafter, hunting may occur by the time when the flow rate approaches the set value. Thus, the separation state may be degraded due to the state in which the flow rate of an eluant in an endless flow passage is out of control (see, for example, FIG. 3 of Patent Literature 3). Examples of a method for preventing such an obstacle to the control include mechanical means for providing a pressure adjustment valve on a discharge side of a pump, a method for changing the rotation number of a pump, a method for controlling the flow rate of a pump based on the difference between a set value and an actually measured value at each of a flow rate of an eluant in an endless flow passage and a pressure on a suction side of the pump (see, for example, Patent Literature 4), and a method for controlling the flow rate of a pump by correcting a control signal based on the set value of a pump and the set value of a pressure on a suction side of the pump, based on the control signal in a state in which an eluant flow stably (see, for example, Patent Literature 3).
However, according to these methods, when the flow rate of an eluant is increased so as to enhance the productivity per SMBC separation system as described above, a switching interval of the control of a pump becomes much shorter, which may make it difficult to control the flow rate of an eluant so that appropriate separation is performed. Such tendency is conspicuous particularly in the SMB method using columns each having a fill length shorter relative to the diameter of the columns as described in Patent Literature 1. As the countermeasures against such tendency, the use of columns having a large ratio of a length to a diameter is considered so as to increase the switching interval of the control of the pump. However, in this case, the pressure loss by the columns increases, and hence, the circulation flow rate of an eluant cannot be increased sufficiently.
Prior Art Literatures
Patent Literature
[PTL 1] WO 01/33210 A1
[PTL 2] JP 51-18392 B
[PTL 3] JP 07-8322 B
[PTL 4] JP 07-8321 B
[PTL 5] JP 2002-82106 A
Non Patent Literature
[NPL 1] Olivier Ludemann-Hombourger et al., “Separation Science and Technology”, 35(9), 2000, p. 1303